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The Genetics of Neurodevelopmental Disorders

The Genetics of Neurodevelopmental Disorders is a new book that will be published by Wiley in 2015. It is due out in August (in Europe) and September (in the USA), and is available on Amazon here.

I had the pleasure of editing the book, which comprises 14 chapters from world-leading scientists and clinicians. Our aim is to provide a timely synthesis of this fast-moving field where so much exciting progress has been made in recent years. Below I have reproduced the Foreword from the book, which outlines the rationale for writing it and the conceptual principles on which it is based, as well as a summary of the topics covered (giving an overview of the state of the field in the process). There are also links to two chapters that are freely available. On behalf of all the authors, I hope the book will prove useful.Foreword

However, the term can be defined
differently, not based on age of onset or clinical presentation, but by an
etiological criterion, to mean disorders arising from aberrant neural
development. This definition includes many forms of epilepsy (considered either
as a distinct disorder or as a co-morbid symptom) as well as disorders like
schizophrenia (SZ), which have later onset but which can still be traced back
to neurodevelopmental origins. Though the symptoms of SZ itself typically arise
only in late teens or early twenties, convergent evidence of epidemiological
risk factors during fetal development and very early deficits apparent in
longitudinal studies strongly indicate that SZ is a disorder of neural
development, though its clinical consequences may remain latent for many years.

Collectively, severe neurodevelopmental
disorders affect ~5% of the population (though exact numbers are almost
impossible to obtain, due to changing diagnostic criteria and substantial
co-morbidity between clinical categories). These disorders impact on the most
fundamental aspects of human experience: cognition, language, social
interaction, perception, mood, motor control,
sense of self. They impair function, often severely,
and restrict opportunities for sufferers, as well as placing a heavy burden on
families and caregivers. As lifelong illnesses, they also give rise to a
substantial economic burden, both in direct healthcare costs and indirect costs
due to lost opportunity.

The treatments currently available for
neurodevelopmental disorders are very limited and problematic. Intensive
educational interventions may help ameliorate some cognitive or behavioural
difficulties, such as those associated with ID or ASD, but to a limited extent
and without addressing the underlying pathology. With respect to psychiatric
symptoms, the mainstays of pharmacotherapy
(antipsychotic medication, mood stabilizers, antidepressants and anxiolytics)
all emerged between the 1940’s and 1960’s with almost no new drugs being
developed since. Most of these treatments were discovered serendipitously, and
their mechanisms of action remain poorly understood. In most cases, the
existing treatments are only partially effective and can induce serious side
effects. This is also true for the range of anticonvulsants, and, for all these
drugs, it is typically impossible to predict from symptom profiles alone whether
individual patients will benefit from a particular drug or possibly be harmed
by it. These difficulties and the attendant poor outcomes for many patients
arise from not knowing the causes of disease in particular patients and not
understanding the underlying pathogenic mechanisms. Genetic research promises
to address both these issues.

Neurodevelopmental disorders are predominantly genetic
in origin and have often been thought of as falling into two groups. The first
includes a very large number of individually rare syndromes with known genetic
causes. Examples include Fragile X syndrome, Down syndrome, Rett syndrome and
Angelman syndrome but there are literally hundreds of others. Each of these is
clearly caused by a single genetic lesion, sometimes involving an entire
chromosome or a section of chromosome, sometimes affecting a single gene. Most
are characterised by ID, but many also show high rates of epilepsy, ASD or
other neuropsychiatric symptoms.

The second group comprises idiopathic cases of ID,
ASD, SZ or epilepsy – those with no currently known cause. Despite the lack of
an identified genetic lesion, there is still very strong evidence of a genetic
etiology across these categories. All of these conditions are highly heritable,
showing high levels of twin
concordance, much higher in monozygotic than in dizygotic twins, substantially increased
risk to relatives and typically zero effect of a shared family environment,
indicating strong genetic causation.

What has not been clear is whether these so-called
“common disorders” are simply collections of rare genetic syndromes that we cannot
yet discriminate, or whether they have a very different genetic architecture. The
dominant paradigm in the field has held that the idiopathic, non-syndromic
cases of common disorders like ASD or SZ reflect the extreme end of a continuum
of risk across the population. This is based on a model involving the
segregation of a very large number of genetic variants, each of small effect
alone, which can, above a collective threshold of burden in individuals, result
in frank disease.

Recent genetic discoveries are prompting a
re-evaluation of this model, as well as casting doubt on the biological
validity of clinical diagnostic categories. After decades of frustration, the
genetic secrets of these conditions are finally yielding to new genomic
microarray and sequencing technologies. These are revealing a growing list of
rare, single mutations that confer high risk of ASD, ID, SZ or epilepsy,
particularly epileptic encephalopathies.

These findings strongly reinforce a model of genetic
heterogeneity, whereby common clinical categories do not represent singular
biological entities, but rather are umbrella terms for a large number of
distinct genetic conditions. These conditions are individually rare but
collectively common. Strikingly, almost all of the identified mutations are
associated with variable clinical manifestations, conferring risk across
traditional diagnostic boundaries. These findings fit with large-scale
epidemiological studies that also show shared risk across these disorders. Thus,
while current diagnostic categories may reflect more or less distinct clinical
states or outcomes, they do not reflect distinct etiologies.

The “genetics of autism” is thus neither singular nor
separable from the “genetics of intellectual disability”, the “genetics of
schizophrenia” or the “genetics of epilepsy”. The more general term of “developmental brain dysfunction” has
been proposed to encompass disorders arising from altered neural development,
which can manifest clinically in diverse ways. This book is about the genetics
of developmental brain dysfunction.

A lot can go wrong in the development of a human
brain. The right numbers of hundreds of distinct types of nerve cells have to
be generated in the right places, they have to migrate to form highly organised
structures, and they must extend nerve fibres, which navigate their way through
the brain to ultimately find and connect with their appropriate partners,
avoiding wrong turns and illicit interactions. Once they find their partners
they must form synapses, the incredibly complex and diverse cellular structures
that mediate communication between nerve cells. These synapses are also highly
dynamic, responding to patterns of activity by strengthening or weakening the
connection.

The instructions to carry out these processes are
encoded in the genome of the developing embryo. Each of these aspects of neural
development requires the concerted action of the protein products of thousands
of distinct genes. Mutations in any one of them (or sometimes in several at the
same time) can lead to developmental brain dysfunction.

The identification of numerous causal mutations has
focused attention on the roles of the genes affected, with a number of
prominent classes of neurodevelopmental genes emerging. These include genes
involved in early brain patterning and proliferation, those mediating later
events of cell migration and axon guidance, and a major class involved in synapse
formation and subsequent activity-dependent synaptic refinement, pruning and
plasticity. Also highlighted are a number of biochemical pathways and networks
that appear especially sensitive to perturbation.

Genetic discoveries thus allow an alternate means to
classify disorders, based on the underlying neurodevelopmental processes
affected. This provides more etiologically valid and arguably more biologically
coherent categories than those based on clinical outcome. For individual
patients, the application of microarray and sequencing technologies is already
changing clinical practice in diagnosis and management of neurodevelopmental
disorders. This will only increase as more and more pathogenic mutations are
identified.

Such discoveries also provide entry points to enable
the elucidation of pathogenic mechanisms, where exciting progress is being made
using cellular and animal models. For any given mutation, this involves
defining the defects at a cellular level (in the right cells), and working out
how such defects propagate to the levels of neural circuits and systems,
ultimately producing pathophysiological states that underlie neuropsychiatric
symptoms. Definition of these pathways will hopefully lead to a detailed enough
understanding of the molecular or circuit-level defects to rationally devise
new therapeutics.

The elucidation of the heterogeneous genetic and
neurobiological bases of neurodevelopmental disorders should thus enable a much
more personalised approach to diagnosis and treatment for individual patients,
and a shift in clinical care for these disorders from an approach based on
superficial symptoms and generic medicines, to one based on detailed knowledge
of specific causes and mechanisms.

The book is organised into several sections:

Chapters
1-6 cover broad conceptual issues relevant to neurodevelopmental disorders in
general. These are informed by recent advances in genomic technologies, which
have transformed our view of the genetic architecture of both rare and
so-called “common” neurodevelopmental disorders. These chapters will consider
the genetic heterogeneity of clinical categories like ASD or SZ, the relative
importance of different types of mutations (common vs rare; single-gene vs
large deletions or duplications; inherited vs de novo), etiological overlap between clinical categories and
complex interactions between two or more mutations or between genetic and
environmental factors.

A preprint of Chapter 1, by me, on The Genetic Architecture of Neurodevelopmental Disorders, is available here.

Chapters
7-9 present our current understanding of several different types of disorder,
grouped by the neurodevelopmental process impacted. Consideration of disorders
from this angle provides a more rational and biologically valid approach than
consideration from the point of view of clinical symptoms, which can be arrived
at through various routes.

Chapters 10-11 deal with the elucidation of pathogenic mechanisms, following genetic
discoveries. They include chapters on cellular models (using induced
pluripotent stem cells derived from patients) and animal models (recapitulating
pathogenic mutations in mice), which are revealing the routes of pathogenesis,
from defects in diverse cellular neurodevelopmental processes to resultant alterations
in neural circuits and brain systems, which ultimately impinge on behaviour. The
manifestation of these defects in humans also depends on processes of learning
and experience-dependent development that proceed for many years after birth. Taking
this aspect of development seriously is essential as it is a critical period
where symptoms can be exacerbated if neglected or potentially improved by
intensive interventions.

Chapters 13-14 consider the clinical implications of recent discoveries and of the
general principles described in earlier chapters. Foremost among these is the
recognition of extreme genetic heterogeneity, meaning that understanding what
is going on in any particular patient requires knowledge of the specific
underlying genetic cause. The dramatic reductions in cost for whole-genome
sequencing mean such diagnoses will become far easier to make, with important
implications for clinical genetic practice (including preimplantation or prenatal
screening or diagnosis). Finally, the study of cellular and animal models of
specific disorders is already suggesting potential therapeutic avenues for some
conditions. These advances illustrate a general principle – to treat these
conditions we need to identify and understand the underlying biology and design
therapies to treat the specific cause in each patient and not just the generic
symptoms.

A preprint of Chapter 13, by Gholson Lyon and Jason O'Rawe, on Human genetics and
clinical aspects of neurodevelopmental disorders
is available here.

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